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EP0427526A1 - Pyridine derivatives, processes for their preparation and pharmaceutical compositions thereof - Google Patents

Pyridine derivatives, processes for their preparation and pharmaceutical compositions thereof Download PDF

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Publication number
EP0427526A1
EP0427526A1 EP90312167A EP90312167A EP0427526A1 EP 0427526 A1 EP0427526 A1 EP 0427526A1 EP 90312167 A EP90312167 A EP 90312167A EP 90312167 A EP90312167 A EP 90312167A EP 0427526 A1 EP0427526 A1 EP 0427526A1
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EP
European Patent Office
Prior art keywords
pyridine
formula
cyanoimino
compound
nitroimino
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EP90312167A
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German (de)
French (fr)
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EP0427526B1 (en
Inventor
György Dr. Domany
Elemér Ezer
Istvan Dr. Schon
Judit Dr. Matuz
Katalin Dr. Saghy
Laszlo Dr. Szporny
György Dr. Hajos
Marta Rényet
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Richter Gedeon Vegyeszeti Gyar Nyrt
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Richter Gedeon Vegyeszeti Gyar RT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms

Definitions

  • the invention relates to pyridine derivatives, processes for their preparation and pharmaceutical compositions thereof.
  • guanidine-type compounds have been disclosed, a subgroup of which consists of (1-methyl-2-pyridylidene)-guanidine derivatives.
  • the substances described in this specification possess hypoglycaemic, secretion-­inhibiting and cardiovascular activities.
  • lower means a carbon chain consisting of 1 to 8 carbon atoms.
  • the gastric acid secretion-inhibiting effect of the compounds according to the present invention was studied using Shay's method [Gastroenterology 56 , pages 5 to 13 (1947)].
  • female H-Wistar rats weighing 120 to 150 g were starved in latticed cages for 24 hours. The animals received water ad libitum . Then their pylori were ligated under a slight ether anaesthesia. The test compounds were administered during the surgical intervention. After 4 hours the animals were killed by ether narcosis. After excision of the stomach, the volume and pH value of the gastric content were measured. In several cases the hydrochloric acid content was determined by titration.
  • ED50mg/kg 1-(2-chlorobenzyl)-2-(cyanoimino)pyridine 1.80
  • 1-benzyl-2-(cyanoimino)pyridine 3.26
  • 2-(cyanoimino)-1-(2-fluorobenzyl)pyridine 4.30
  • 2-(cyanoimino)-1-(4-fluorobenzyl)pyridine 8.36
  • 1-(3-chlorobenzyl)-2-(cyanoimino)pyridine 9.88 2-(cyanoimino)-1-(2-methylbenzyl)pyridine 11.70
  • 2-(cyanoimino)-1-(3-trifluoromethylbenzyl)pyridine 12.20
  • benzyl-2-(nitroimino)pyridine 13.55
  • the oral ED50 value of cimetidine (chemically 1-cyano-2-methyl-3-[2-[ [(5-methylimidazol-­4-yl)methyl]thio]ethyl)-guanidine) in the same test is 50 mg/kg.
  • a 50 mg/kg oral dose of 1-benzyl-2-(cyanoimino)­pyridine inhibits the development of gastric ulcers induced in rats by a 40 mg/kg subcutaneous (s.c.) dose of indomethacine (chemically [1-(4-chlorobensoyl)-2-­methyl-5-methoxyindol-3-yl) acetic acid) by l00%.
  • indomethacine chemically [1-(4-chlorobensoyl)-2-­methyl-5-methoxyindol-3-yl) acetic acid
  • the reaction according to process a) above is preferably carried out in a protic or dipolar aprotic solvent.
  • a protic or dipolar aprotic solvent Preferable solvents include lower alkanols such as ethanol; lower ketones such as acetone or lower alkanenitriles such as acetonitrile.
  • the 2-iminopyridine derivative of formula (II) used as starting material may be optionally prepared in situ by the alkaline treatment of a pyridinium salt of the general formula (VI), wherein X1 and X2 are as defined above and Y represents a halide ion.
  • the alkaline treatment is carried out with a base.
  • reaction with cyanogen bromide is carried out in the presence of an organic base (as an acid binding agent), then 1 mole of cyanogen bromide should be used for every 1 mole of the 2-iminopyridine derivative of formula (II) used. However, if this reaction is carried out without any acid binding agent, only 0.5 mole of cyanogen bromide should be used for every 1 mole of the 2-iminopyridine derivative of formula (II). This reaction is preferably carried out in an ether-type solvent.
  • This invention also relates to use of a compound of formula (I) as defined hereinabove in the manufacture of a medicament for the gastric acid secretion-inhibiting, tissue-protecting, pain relieving and mild anti-­inflammatory treatment of mammals.
  • a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore in admixture with a pharmaceutically acceptable carrier and/or additive.
  • the following compounds may be prepared in a manner analogous to the above process: 1-(2-fluorobenzyl)-2-(nitroimino)pyridine, m.p.: 165-166 o C (from ethanol), 1-(2-chlorobenzyl)-2-(nitroimino)pyridine, m.p.: 185-186 o C (from acetonitrile), 1-(4-chlorobenzyl)-2-(nitroimino)pyridine, m.p..
  • the isomeric by-product i.e. N-benzyl-N-cyano-2-­pyridylamine, m.p.: 65-66°C (from ethanol), may be obtained from the ethereal filtrate by purification with column chromatography.
  • the following compounds may be prepared in a manner analogous to the above process: 2-(cyanoimino)-1-(2-fluorobenzyl)pyridine, m.p.: 157-158 o C (from isopropanol), 1-(2-chlorobenzyl)-2-(cyanoimino)pyridine, m.p.: 167-168 o C (from ethanol), 2-(cyanoimino)-1-(4-fluorobenzyl)pyridine, m.p.: 147-148 o C (from isopropanol), 1-(4-chlorobenzyl)-2-(cyanoimino)pyridine, m.p.: 168-170 o C (from isopropanol), 1-(4-bromobenzyl)-2-(cyanoimino)pyridine, m.p.: 168-170 o C (from ethanol), 2-(cyanoimino)-1-(4-nitrobenzy
  • active ingredient i.e. a compound of the present invention
  • active ingredient i.e. a compound of the present invention
  • 285.0 g lactose 100.0 g of potato starch
  • 2.5 g of sodium dodecyl sulfate 5.0 g of polyvinylpyrrolidone (Kollidon-K 90 R )
  • 50.0 g of microcrystalline cellulose Avicel R
  • 7.5 g of vegetable oil sterotex R
  • the tablets prepared as described above are coated in a known manner with a layer consisting of sugar and talc, then the dragees obtained are polished with a mixture of bees wax and carnauba wax.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to pyridine derivatives of formula (I),
Figure imga0001
 wherein
Q represents a nitro or cyano group; and
X¹ and X², which may be the same or different, represent a hydrogen or halogen atom, or a trifluoromethyl, a lower alkyl, alkoxy or nitro group, bound to any of the carbon atoms of the phenyl ring.
The invention further relates to pharmaceutical compositions containing these compounds and processes for their preparation.
The compounds of formula (I) possess gastric acid secretion inhibiting, tissue-protecting, analgesic and mild antiinflammatory effects and are useful for therapeutical purposes.

Description

  • The invention relates to pyridine derivatives, processes for their preparation and pharmaceutical compositions thereof.
  • The biological activity of a few known pyridine compounds, being structurally similar to the compounds of the present invention, is known. For example, the alkylation on the ring nitrogen of 2-(nitroamino)pyridine by α-halo-ketones, α-haloesters and phenylethyl halides has been described in: J. Med. Chem. 14, 988 (1971) and the anti-inflammatory effect of the compounds obtained has also been described.
  • In European patent specification No. 9,362 (1980), guanidine-type compounds have been disclosed, a subgroup of which consists of (1-methyl-2-pyridylidene)-guanidine derivatives. The substances described in this specification possess hypoglycaemic, secretion-­inhibiting and cardiovascular activities.
  • Among the insecticidal compounds described in published Japanese patent applications Nos. 63-­307,857(1988) and 63-287,764 (1988) as well as in the published European patent application No. 0,259,738 (1988), 2-(cyanoimino)- and 2-(nitroimino)pyridines substituted on the ring nitrogen by a cyanoalkyl or 3-­cyanobenzyl group or by a heterocyclic group through the methylene group have also been described.
  • We have developed a new range of compounds which possess important biological actions. The most important of these are an inhibition of gastric acid secretion and a tissue-protecting effect. Several of these new compounds also exert analgesic and mild antiinflammatory effects.
  • According to one aspect of the present invention, there are provided compounds of formula (I)
    Figure imgb0001
     wherein
    Q represents a nitro or cyano group; and
    X¹ and X², which may be the same or different, represent a hydrogen or halogen atom, or a trifluoromethyl, a lower alkyl, alkoxy or nitro group, bound to any of the carbon atoms of the phenyl ring.
  • As used herein, the term "lower" means a carbon chain consisting of 1 to 8 carbon atoms.
  • The gastric acid secretion-inhibiting effect of the compounds according to the present invention was studied using Shay's method [Gastroenterology 56, pages 5 to 13 (1947)]. According to this method female H-Wistar rats weighing 120 to 150 g were starved in latticed cages for 24 hours. The animals received water ad libitum. Then their pylori were ligated under a slight ether anaesthesia. The test compounds were administered during the surgical intervention. After 4 hours the animals were killed by ether narcosis. After excision of the stomach, the volume and pH value of the gastric content were measured. In several cases the hydrochloric acid content was determined by titration.
  • The ED₅₀ values of some of the compounds of the invention (given as mg/kg) determined in the above test are as follows:
    ED₅₀mg/kg
    1-(2-chlorobenzyl)-2-(cyanoimino)pyridine 1.80
    1-benzyl-2-(cyanoimino)pyridine 3.26
    2-(cyanoimino)-1-(2-fluorobenzyl)pyridine 4.30
    2-(cyanoimino)-1-(4-fluorobenzyl)pyridine 8.36
    1-(3-chlorobenzyl)-2-(cyanoimino)pyridine 9.88
    2-(cyanoimino)-1-(2-methylbenzyl)pyridine 11.70
    2-(cyanoimino)-1-(3-trifluoromethylbenzyl)pyridine 12.20
    1-benzyl-2-(nitroimino)pyridine 13.55
  • As a comparison, the oral ED₅₀ value of cimetidine (chemically 1-cyano-2-methyl-3-[2-[ [(5-methylimidazol-­4-yl)methyl]thio]ethyl)-guanidine) in the same test is 50 mg/kg..
  • A 50 mg/kg oral dose of 1-benzyl-2-(cyanoimino)­pyridine inhibits the development of gastric ulcers induced in rats by a 40 mg/kg subcutaneous (s.c.) dose of indomethacine (chemically [1-(4-chlorobensoyl)-2-­methyl-5-methoxyindol-3-yl) acetic acid) by l00%.
  • No toxic symptom was induced in rats by a single oral dose of 120 mg/kg of each test compound of the invention.
  • According to another aspect of the present invention, there is provided a process for the preparation of the pyridine derivatives of the general formula (I), which comprises
    • a) reacting a 2-(substituted amino) pyridine derivative of formula (III),
      Figure imgb0002
       wherein Q is as hereinbefore defined, with a benzyl halide of formula (IV),
      Figure imgb0003
       wherein X¹ and X² are as hereinbefore defined and W represents a chlorine or bromine atom, in the presence of an organic or inorganic base, followed by separating the pyridine derivative of formula (I) so obtained, from the isomeric pyridine derivative of formula (V),
      Figure imgb0004
       wherein, Q, X¹ and X² are as defined above which is formed as a by-product of the reaction;
      or
    • b) for compounds wherein Q is a cyano group only, reacting cyanogen bromide with a 2-iminopyridine derivative of formula (II),
      Figure imgb0005
       wherein X¹ and x² are as defined above.
  • The reaction according to process a) above is preferably carried out in a protic or dipolar aprotic solvent. Preferable solvents include lower alkanols such as ethanol; lower ketones such as acetone or lower alkanenitriles such as acetonitrile.
  • In process b) above the 2-iminopyridine derivative of formula (II) used as starting material may be optionally prepared in situ by the alkaline treatment of a pyridinium salt of the general formula (VI),
    Figure imgb0006
     wherein X¹ and X² are as defined above and Y represents a halide ion.
  • Preferably, the alkaline treatment is carried out with a base.
  • If the reaction with cyanogen bromide is carried out in the presence of an organic base (as an acid binding agent), then 1 mole of cyanogen bromide should be used for every 1 mole of the 2-iminopyridine derivative of formula (II) used. However, if this reaction is carried out without any acid binding agent, only 0.5 mole of cyanogen bromide should be used for every 1 mole of the 2-iminopyridine derivative of formula (II). This reaction is preferably carried out in an ether-type solvent.
  • This invention also relates to use of a compound of formula (I) as defined hereinabove in the manufacture of a medicament for the gastric acid secretion-inhibiting, tissue-protecting, pain relieving and mild anti-­inflammatory treatment of mammals.
  • According to a further feature of the present invention, we provide a pharmaceutical composition which comprises a compound of formula (I) as defined hereinbefore in admixture with a pharmaceutically acceptable carrier and/or additive.
  • The invention is illustrated by way of the following non-limiting Examples and Pharmaceutical Preparations.
    • Example 1 1-benzyl-2-(nitroimino)pyridine
  • 20 ml (0.114 mole) of N,N-diisopropylethylamine and 12 ml (0.1 mole) of benzyl bromide are added to a suspension containing 14 g (0.1 mole) of 2-(nitroamino)­pyridine [prepared according to J. Am. Chem. Soc. 77, 3154 (1955)] in 100 ml of acetonitrile, then the mixture is refluxed for 2.5 hours. The reaction mixture is cooled down then evaporated under reduced pressure, the residue is triturated with water, the suspension obtained is filtered and washed with water. The filter cake is thoroughly sucked, then suspended in 50 ml of petroleum ether, filtered and washed again with petroleum ether to give 14.2 g (62%) of the title product, m.p.: 125-126°C (recrystallized from ethyl acetate).
  • From the petroleum ether filtrate the isomeric by-­product, i.e. N-benzyl-N-nitro-2-pyridylamine hydrochloride, m.p.: 115-116°C (recrystallized from ethyl acetate) can be obtained by column chromatography and salt formation with hydrochloric acid.
  • Using the appropriate starting materials, the following compounds may be prepared in a manner analogous to the above process:
    1-(2-fluorobenzyl)-2-(nitroimino)pyridine, m.p.: 165-166 oC (from ethanol),
    1-(2-chlorobenzyl)-2-(nitroimino)pyridine, m.p.: 185-186 oC (from acetonitrile),
    1-(4-chlorobenzyl)-2-(nitroimino)pyridine, m.p.. 164-165 oC (from ethanol),
    1-(4-bromobenzyl)-2-(nitroimino)pyridine, m.p.: 184-185 oC (from acetonitrile) and
    1-(4-nitrobenzyl)-2-nitroimino)pyridine, m.p.: 224-225°C (from acetronitrile).
    • Example 2 1-benzyl-2-(cyanoimino)pyridine
  • 20 ml (0.114 mole) of N,N-diisopropylethylamine and 12 ml (0.1 mole) of benzyl bromide are added to a suspension containing 12 g (0.1 mole) of 2-(cyanoamino)­pyridine [prepared according to Ann. Phar. Fr. 26, 469 (1968)] in 100 ml of acetonitrile. The reaction mixture is refluxed for 4 hours, then cooled down and evaporated under reduced pressure. The residue is triturated with water, filtered and washed with water. The filter cake is thoroughly sucked, then suspended in 30 ml of ether, filtered and washed again with ether to yield 11.0 g (52.6%) of the title compound, m.p.: 147-148°C (from ethanol).
  • The isomeric by-product i.e. N-benzyl-N-cyano-2-­pyridylamine, m.p.: 65-66°C (from ethanol), may be obtained from the ethereal filtrate by purification with column chromatography.
  • Using the appropriate starting materials, the following compounds may be prepared in a manner analogous to the above process:
    2-(cyanoimino)-1-(2-fluorobenzyl)pyridine, m.p.: 157-158 oC (from isopropanol),
    1-(2-chlorobenzyl)-2-(cyanoimino)pyridine, m.p.: 167-168 oC (from ethanol),
    2-(cyanoimino)-1-(4-fluorobenzyl)pyridine, m.p.: 147-148 oC (from isopropanol),
    1-(4-chlorobenzyl)-2-(cyanoimino)pyridine, m.p.: 168-170 oC (from isopropanol),
    1-(4-bromobenzyl)-2-(cyanoimino)pyridine, m.p.: 168-170 oC (from ethanol),
    2-(cyanoimino)-1-(4-nitrobenzyl)pyridine, m.p.: 208-210 oC (from ethanol),
    2-(cyanoimino)-1-(2,6-dichlorobenzyl)pyridine, m.p.: 219-220 oC (from ethanol),
    2-(cyanoimino)-1-(2-nitrobenzyl)pyridine, m.p.: 197-199 oC (from acetonitrile),
    2-(cyanoimino)-1-(2-methylbenzyl)pyridine, m.p.: 152-154 oC (from acetonitrile),
    2-(cyanoimino)-1-(3-methoxybenzyl)pyridine, m.p.: 133-135 oC (from methanol),
    2-(cyanoimino)-1-(4-methylbenzyl)pyridine, m.p.: 173-174 oC (from ethanol),
    1-(3-chlorobenzyl)-2-(cyanoimino)pyridine, m.p.: 175-176 oC (from methanol) and
    2-(cyanoimino)-1-(3-trifluoromethylbenzyl)pyridine, m.p.: 144-145 oC (from ethanol).
    • Example 3 1-benzyl-2-(cyanoimino)pyridine
  • 7 g (50 mmole) of potassium carbonate and 6.5 ml (55 mmole) of benzyl bromide are added to a suspension of 6 g (50 mmole) of 2-(cyanoamino)pyridine in 100 ml of acetone, then the reaction mixture is refluxed under vigorous stirring for 2.5 hours. After cooling down the inorganic salt is filtered off and the acetone filtrate is evaporated under reduced pressure. The residue is triturated with 10 ml of ether, filtered and washed twice with 5 ml of ether each to obtain 5.55 g (53. 1%) of the title compound, m.p.: 142°C.
    • Example 4 1-benzyl-2-(cyanoimino)pyridine
  • 5.3 g (20 mmole) of 2-amino-1-benzylpyridinium bromide [prepared according to Chem. Ber. 88, 1103 (1955)] are suspended in 20 ml of ether, then 20 ml of aqueous sodium hydroxide solution of 0.5 mole litre concentration are added while stirring. After the dissolution of the solid phase the phases are separated and the aqueous phase is extracted with 20 ml of ether. The combined organic phase is dried over anhydrous sodium sulphate and evaporated to half its volume under reduced pressure. Then, a solution containing 1.1 g (10 mmole) of cyanogen bromide in 5 ml of ether is dropped into the ethereal solution at room temperature under stirring. After stirring for 30 minutes the crystalline precipitate is filtered, washed with ether and then with water, then the product is air dried to yield 0.91 g (44%) of the title product, m.p.: 139-140°C (after recrystallization from ethanol the melting point rises to 147-148°C). On the basis of its melting point, infrared spectrum and thin layer chromatography (TLC) characteristics, this product proved to be identical to the target compound of Example 2.
    • Pharmaceutical Preparations a) Preparation of tablets of a weight of 100 mg containing 10 mg of active ingredient each
  • 50.0 g of active ingredient i.e. a compound of the present invention, is mixed together with 285.0 g lactose, 100.0 g of potato starch, 2.5 g of sodium dodecyl sulfate, 5.0 g of polyvinylpyrrolidone (Kollidon-K 90R), 50.0 g of microcrystalline cellulose (AvicelR) and 7.5 g of vegetable oil (sterotexR) and after wet granulation, the product obtained is compressed into tablets weighing 100 mg each. Each of the tablets contains 10 mg of active ingredient.
    • b) Preparation of dragees of a weight of 125 mg containing 10 mg of active ingredient each
  • The tablets prepared as described above are coated in a known manner with a layer consisting of sugar and talc, then the dragees obtained are polished with a mixture of bees wax and carnauba wax.
    • c) Preparation of capsules containing 20 mg of active ingredient each
  • 40.0 g of active ingredient, 12.0 g of sodium lauryl sulfate, 102.0 g of lactose, 102.0 g of potato starch, 2.4 g of magnesium stearate and 1.6 g of colloidal silicon dioxide are thoroughly mixed together and the mixture obtained is filled into hard gelatine capsules containing 20 mg of active ingredient each.

Claims (10)

1. A novel compound of formula (I),
Figure imgb0007
 wherein
Q represents a nitro or cyano group; and
X¹ and X², which may be the same or different, represent a hydrogen or halogen atom, or a trifluoromethyl, a lower alkyl, alkoxy or nitro group, bound to any of the carbon atoms of the phenyl ring.
2. A compound of formula (I) as defined in Claim 1 selected from the group comprising
1-benzyl-2-(nitroimino)pyridine,
1-(2-fluorobenzyl)-2-(nitroimino)pyridine,
1-(2-chlorobenzyl)-2-(nitroimino)pyridine,
1-(4-chlorobenzyl)-2-(nitroimino)pyridine,
1-(4-bromobenzyl)-2-(nitroimino)pyridine,
1-(4-nitrobenzyl)-2-(nitroimino)pyridine,
1-benzyl-2-(cyanoimino)pyridine,
2-(cyanoimino)-1-(2-fluorobenzyl)pyridine,
1-(2-chlorobenzyl)-2-(cyanoimino)pyridine,
1-(3-chlorobenzyl)-2-(cyanoimino)pyridine,
2-(cyanomino)-1-(3-methoxybenzyl)pyridine,
2-(cyanomino)-1-(3-trifluoromethylbenzyl)pyridine,
2-(cyanoimino)-1-(2-methylbenzyl)pyridine,
2-(cyanoimino)-1-(4-methylbenzyl)pyridine,
2-(cyanoimino)-1-(4-fluorobenzyl)pyridine,
1-(4-chlorobenzyl )-2-(cyanoimino)pyridine,
1-(4-bromobenzyl)-2-(cyanoimino)pyridine,
2-(cyanoimino)-1-(2-nitrobenzyl)pyridine,
2-(cyanoimino)-1-(4-nitrobenzyl)pyridine and
2-(cyanoimino)-1-(2,6-dichlorobenzyl)pyridine
3. A pharmaceutical composition which comprises a compound of formula (I) as defined in Claim 1 in admixture with a pharmaceutically acceptable carrier and/or additive.
4. A process for the preparation of a compound of formula (I) as defined in Claim 1 which comprises
a) reacting a 2-(substituted amino) pyridine derivative of formula (III),
Figure imgb0008
 wherein Q is as defined in Claim 1, with a benzyl halide of formula (IV),
Figure imgb0009
 wherein X¹ and X² are as defined in Claim 1 and W represents a chlorine or bromine atom, in the presence of an organic or inorganic base, followed by separating the pyridine derivative of formula (I) so obtained, from the isomeric pyridine derivative of formula (V),
Figure imgb0010
 wherein, Q, X¹ and X² are as defined above, which is formed as a by-product of the reaction;
or
b) for compounds wherein Q is a cyano group only, reacting cyanogen bromide with a 2-iminopyridine derivative of formula (II),
Figure imgb0011
 wherein X¹ and X² are as defined above.
5. A process as claimed in process a) of Claim 4 wherein W is a bromine atom.
6. A process as claimed in process a) of claim 4 or Claim 5 wherein the base is tri(lower alkyl)amine.
7. A process as claimed in process a) of Claim 4 or Claim 5 wherein the base is an alkaline metal carbonate.
8. A process as claimed in process a) of claim 4 or any one of Claims 5, 6 or 7, wherein the reaction of a compound of formula (III) with a compound of formula (IV) is carried out in a dipolar aprotic solvent.
9. A process as claimed in process b) of Claim 4 wherein the compound of formula (II) is prepared in situ by the alkaline treatment of a pyridinium salt of the general formula (VI),
Figure imgb0012
 wherein X¹ and X² are as defined in Claim 1 and Y represents a halide ion.
10. The use of a compound of formula (I) as defined in Claim 1 in the manufacture of a medicament for the gastric acid secretion-inhibiting, tissue-protecting, pain relieving and mild anti-inflammatory treatment of mammals.
EP90312167A 1989-11-07 1990-11-07 Pyridine derivatives, processes for their preparation and pharmaceutical compositions thereof Expired - Lifetime EP0427526B1 (en)

Applications Claiming Priority (2)

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HU580789 1989-11-07
HU895807A HU207047B (en) 1989-11-07 1989-11-07 Process for producing new pyridine derivatives and pharmaceutical copositions comprising same

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US6297375B1 (en) 1999-02-24 2001-10-02 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US7288658B2 (en) 2003-07-15 2007-10-30 Hoffmann-La Roche Inc. Process for preparation of pyridine derivatives
US8852634B2 (en) 2005-09-23 2014-10-07 Hoffmann-La Roche Inc. Dosage formulation
WO2020030503A1 (en) 2018-08-07 2020-02-13 Syngenta Crop Protection Ag Pesticidally-active bicyclic heteroaromatic compounds
WO2020120697A1 (en) 2018-12-14 2020-06-18 Syngenta Crop Protection Ag Pesticidally-active cyanamide heterocyclic compounds
WO2020169526A1 (en) 2019-02-18 2020-08-27 Syngenta Crop Protection Ag Pesticidally-active cyanamide heterocyclic compounds

Families Citing this family (2)

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Publication number Priority date Publication date Assignee Title
AU2011297160B2 (en) * 2010-08-31 2014-11-20 Mitsui Chemicals Crop & Life Solutions, Inc. Noxious organism control agent
MY184642A (en) * 2011-08-26 2021-04-13 Meiji Seika Pharma Co Ltd Method for producing pest control agent

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GB2140412A (en) * 1983-03-16 1984-11-28 Richter Gedeon Vegyeszet Thiazolidine derivatives, process for the preparation and pharmaceutical compositions thereof
EP0259738A2 (en) * 1986-09-10 1988-03-16 Nihon Tokushu Noyaku Seizo K.K. Heterocyclic compounds

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GB2140412A (en) * 1983-03-16 1984-11-28 Richter Gedeon Vegyeszet Thiazolidine derivatives, process for the preparation and pharmaceutical compositions thereof
EP0259738A2 (en) * 1986-09-10 1988-03-16 Nihon Tokushu Noyaku Seizo K.K. Heterocyclic compounds

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6297375B1 (en) 1999-02-24 2001-10-02 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US6479483B2 (en) 1999-02-24 2002-11-12 Hoffmann-La Roche Inc. 4-phenyl-pyridine derivatives
US7288658B2 (en) 2003-07-15 2007-10-30 Hoffmann-La Roche Inc. Process for preparation of pyridine derivatives
US8852634B2 (en) 2005-09-23 2014-10-07 Hoffmann-La Roche Inc. Dosage formulation
WO2020030503A1 (en) 2018-08-07 2020-02-13 Syngenta Crop Protection Ag Pesticidally-active bicyclic heteroaromatic compounds
WO2020120697A1 (en) 2018-12-14 2020-06-18 Syngenta Crop Protection Ag Pesticidally-active cyanamide heterocyclic compounds
WO2020169526A1 (en) 2019-02-18 2020-08-27 Syngenta Crop Protection Ag Pesticidally-active cyanamide heterocyclic compounds

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US5155123A (en) 1992-10-13
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IL96252A (en) 1994-12-29
DK0427526T3 (en) 1994-08-29
NO177263C (en) 1995-08-16
NO904822D0 (en) 1990-11-06
EP0427526B1 (en) 1994-07-27
DE69011046D1 (en) 1994-09-01
KR910009663A (en) 1991-06-28
AU6582390A (en) 1991-05-23
ES2057441T3 (en) 1994-10-16
PH27440A (en) 1993-07-02
ZA908889B (en) 1991-10-30
AR248394A1 (en) 1995-08-18
ATE109137T1 (en) 1994-08-15
CN1052305A (en) 1991-06-19
AU631261B2 (en) 1992-11-19
CA2029222A1 (en) 1991-05-08
HUT55758A (en) 1991-06-28
JPH03169862A (en) 1991-07-23
NO904822L (en) 1991-05-08
HU207047B (en) 1993-03-01
NZ235984A (en) 1992-08-26
DE69011046T2 (en) 1994-11-24
IL96252A0 (en) 1991-08-16

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